The gag proteins of SIV include the p8 Nucleocapsid protein, which contains two cysteine arrays that are involved in viral RNA packaging and in a post-penetration step. Mutations in these arrays render the virus non-infectious. A deletion mutant (M14) of a molecular clone of SIVMne CL8 has been constructed that has a four amino acid deletion in the second cysteine array. This study is designed to test the efficacy of DNA immunizations in the SIV macaque model by immunizing macaques with DNA from the non-infectious viral construct, M14 , as a potential AIDS vaccine. Five macaques received mutant virus DNA and four macaques (controls) were injected with vector plasmid DNA lacking the SIV construct. By SIV ELISA, antibody was detected after DNA immunizations, thus indicating that the mutant proviral DNA was expressed. None of the DNA-inoculated macaques showed any signs of a productive SIV infection, indicating that the DNA construct is safe and does not lead to an est ablished i nfection. Upon challenge, all 4 control macaques became infected. Plasma virus was readily detected by QC-PCR assays at high levels (105-106 genome equivalents/ml) and virus was readily isolated from all 4 of these control macaques. Of the 5 DNA-immunized macaques, no virus was detected in one animal by either virus isolation or QC-PCR. Three of the macaques became infected but the virus levels were less than in controls as determined by virus isolation and plasma RNA assays. Virus load in one immunized animal was indistinguishable from those in the control macaques. Of the original 9 macaques, 7 were still alive in 1998; two control macaques developed clinical AIDS and were euthanized. The remaining macaques are being monitored every other month. FUNDING NIH grant RR00166 and SAIC (Science Applications International Corp.) grant 5S-1530.